Using the Drosophila system, our research goal is to understand cell biology events elicited by cancer-causing genes. My group is focusing on the following two projects: (1) the JAK/STAT signal transduction pathway in Drosophila development and tumor formation; and (2) the epithelial cell sheet movement during Drosophila embryonic dorsal closure. I. The Drosophila JAK/STAT signal transduction pathway The JAK/STAT cascade has emerged as an essential reutilized facet of vertebrate signaling through a large number of cytokines and growth factors. Both decreases and increases in activity of this signaling pathway have severe consequences. Constitutive activation of JAKs and or STATs is correlated with several oncogenic transformations. In 1996, as a postdoctoral fellow in Dr. Norbert Perrimon's laboratory, I isolated the Drosophila STAT mutation (Hou et al., 1996). Overexpression of upd (pGMR-upd), the ligand of the Drosophila JAK/STAT signal transduction pathway, in the fly eye resulted in large deformed eyes. In a genetic screen for suppressors of the abnormal eye phenotype, we identified a receptor (named master of marelle or mom) of the JAK/STAT signal transduction pathway (Chen et al., 2002). In our recent GLC screen, we took advantage of the available complete Drosophila genomic sequence. We first performed a P element-mediated gene disruption screen. By examining over 50,000 mutant lines, we isolated 2,500 single P-insertion lethal mutants. Sequences flanking >2300 insertions were determined that identify 850 different genes or ESTs (Oh et al., 2002). We then performed GLC assays for 600 selected genes whose mutations had not been studied prior to our P-element screen. From the GLC screen, several new genes, "hop-like" genes, have been identified that appear to be part of the JAK/STAT pathway. The Drosophila cyclin-dependent kinase 4 (Cdk4) is among these new genes. We demonstrated that Cyclin D-Cdk4 (and also Cyclin E-Cdk2) binds and regulates STAT92E protein stability (Chen et al., 2003). We further showed that the JAK/STAT signaling and CycD-Cdk4 signaling synergistically regulate melanotic tumor formation. In the eye, the CycD-Cdk4 signaling prevents cell differentiation and the JAK/STAT signaling promotes cell proliferation; collaboration between these two signals leads to the eye's "tumor-like" outgrowth. We have cloned two SOCS genes from Drosophila, socs44A and socs60E. Our results suggest that SOCS60E specifically down-regulates the JAK/STAT signaling and SOCS44A mostly regulates other signalings. II. The epithelial cell sheet movement during Drosophila embryonic dorsal closure In many epithelial-derived cancers, signals will eventually cause cell polarity changes and breakdown of cell junctions, which are the initial steps of tumor metastasis. Drosophila embryonic dorsal closure (DC) mimics these events and provides an excellent system to understand the molecular mechanisms of these processes. DC is also being used as a model system to study wound healing. In DC, actin dynamics at the leading edge are preceded by a polarization of the dorsal-most epidermal cells associated with a reorganization of the cytoskeleton. In 1997, we discovered the Drosophila homologue of the mammalian proto-oncogene c-Jun gene (Djun) as a central regulator of the DC process (Hou et al., 1997). We recently characterized another gene that regulates the DC process, connector of kinase to AP-1 (cka). cka encodes a protein containing several protein-protein interaction domains. CKA forms a complex with HEP (DJNKK), BSK (DJNK), DJUN, and DFOS. The complex activates BSK kinase, which phosphorylates and activates DJUN and DFOS. CKA represents a novel molecule regulating AP-1 activity by organizing a molecular complex of kinases and transcription factors (Chen et al., 2002).